This application proposes to study a recently discovered novel mechanism by which neurotransmitters (NTs) regulate the character and magnitude of T helper (Th) cell responses. Preliminary data demonstrate that NTs can act on endothelial cells (ECs), which then direct the types of immune responses generated in the course of antigen presentation by Langer- hans cells (LCs) to T cells. This novel concept is based on preliminary data showing that exposure of ECs to either (a) the neuropeptide calcitonin gene-related peptide (CGRP) (acting through the CGRP type 1 receptor) or (b) the adrenergic NT norepinephrine (NE), prior to addition to cultures of LCs presenting Ag to T cells, results in an increase in the release of IL-17A (a key cytokine in the pathophysiology of psoriasis) and a decrease in interferon-?. Bias of Ag presentation toward an IL-17A response via NE or CGRP effects on ECs may explain exacerbation of Th17 cell-mediated diseases by stress. Innervation of dermal blood vessels, lymphatics (probably) and lymph nodes by both sensory and sympathetic nerves provides an anatomic substrate by which NTs can impact immune cells via ECs. The in vivo relevance of this pathway is supported by the observation that innervation of the skin is important for the expression of human psoriasis and that the rash in murine models of psoriasiform dermatitis depends on innervation. The discovery of this regulatory pathway may have important implications for a more complete understanding of cutaneous immunity, particularly in pathologic states. We hypothesize that the nervous system regulates the immune system toward particular types of responses by regulating the differentiation pathway of responsive CD4+ T cells through release of NTs acting on EC targets. We will explore this hypothesis in 2 aims: Aim 1A. To determine if CGRP, PACAP, VIP, NE or EPI regulate the outcome of Ag presentation by LCs to responsive CD4+ T cells through actions on ECs. We will test the generality of the hypothesis by studying other relevant skin Ag presenting cells, including dermal dendritic cells (DDCs) and monocyte-derived DCs (as a surrogate for inflammatory dermal DCs). Aim1B. To identify the cell and molecular biologic events in ECs induced by NTs that regulate Th cell differentiation during Ag presentation. We will test the importance of secreted molecules and cell-cell contact. Aim 2: To test the in vivo relevance of NT-induced EC signaling through the use of inducible, conditional KO mice where the expression of the relevant NT receptors is inactivated in EC. As we have determined that the CGRP type 1 receptor mediates the effect of CGRP in this pathway, we will initially generate mice in which we can incactivate the CGRP type 1 receptor and test the role of signaling through this receptor on immune responsiveness and on the development of rash in a a model of psoriasiform dermatitis. These studies will provide insight into the role of the nervous system in regulating skin immune responses, providing a better understanding of pathophysiology in the skin and creating a rational basis for developing drugs that can modulate skin immune responses, including some that may act via EC receptors. Since vessels in many tissues are innervated, our work may serve as a paradigm for the regulation of immune function in other tissues. It will enhance our appreciation of interactions between the nervous and immune systems, and may provide insights into autoimmune disorders and regulation of the immune response to cancer.